Variant classification summary

NM_000546.6:c.527G>T

TP53 · NP_000537.3:p.(Cys176Phe) · NM_000546.6

GRCh37: chr17:7578403 C>A · GRCh38: chr17:7675085 C>A

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PS3 moderate PM2 supporting PP3 moderate

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Cys176Phe)

gnomAD AF

1.2389746741186864e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: the VCEP worksheet records partial function in Kato data and loss of function in three other eligible assays.

2

PM2 supporting: gnomAD v4.1 allele frequency is 1.23897e-06, below the TP53 VCEP threshold.

3

PP3 moderate: the exact VCEP lookup row pre-assigns PP3_moderate for c.527G>T/p.Cys176Phe with BayesDel 0.579613.

Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 point-based rule, PS3 moderate contributes 2 points, PM2 supporting contributes 1 point, and PP3 moderate contributes 2 points; the total of 5 points maps to VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.527G>T is a missense variant yielding p.Cys176Phe, not a TP53 VCEP-defined null or canonical splice variant eligible for PVS1.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	Not assessed	Not assessed: no qualifying independent variant with a different nucleotide change producing the same p.Cys176Phe amino-acid substitution was identified.	cspec clinvar
PS2	Not assessed	Not assessed: no confirmed de novo proband, parental testing, or TP53 VCEP PS2 point assignment is documented for this variant.	cspec
PS3	Met	Met at moderate: the VCEP worksheet assigns C176F PS3_Moderate, with partially functional Kato results and loss of function in three other eligible assays.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet cspec PMID:22090360
PS4	Not assessed	Not assessed: the exact-variant tumor reports lack germline status and the VCEP-defined PS4 cancer-point total needed to reach the >=1-point threshold.	cspec vcep_ps4_points_table PMID:15611505
PM1	Not assessed	Not assessed: p.Cys176Phe is outside the VCEP codon list, while the partial C176 hotspot record lacks the required same-amino-acid count of at least 10.	cspec PMID:10713666 PMID:15037740
PM2	Met	Met at supporting: gnomAD v4.1 AF is 1.23897e-06, below the TP53 VCEP PM2 threshold of 0.00003.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: the TP53 VCEP explicitly excludes PM3 for Li-Fraumeni syndrome, regardless of phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: the TP53 VCEP explicitly designates PM4 as Not Applicable, and c.527G>T is a missense substitution rather than a protein-length-altering indel.	cspec
PM5	Not assessed	Not assessed: no qualifying different missense substitution at Cys176 with a VCEP-concordant pathogenic or clinically supported likely pathogenic classification was identified.	cspec PMID:10713666 PMID:15037740
PM6	N/A	Not applicable: the TP53 VCEP explicitly drops PM6 and uses PS2 exclusively for de novo evidence.	cspec
PP1	Not assessed	Not assessed: no affected relatives, family genotypes, or counted cosegregating meioses are documented for this variant.	cspec
PP2	N/A	Not applicable: the TP53 VCEP explicitly excludes PP2 for this gene.	cspec
PP3	Met	Met: the TP53 VCEP lookup pre-assigns PP3_moderate for c.527G>T / p.Cys176Phe with BayesDel score 0.579613 and C65 classification.	cspec vcep_pp3_bp4_codes bayesdel
PP4	Not assessed	Not assessed: no qualifying multigene-panel VAF observation between 5% and 35% is documented for this TP53 variant.	cspec
PP5	N/A	Not applicable: the TP53 VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum population FAF is 2.8e-07, below the TP53 VCEP BA1 threshold of 0.001.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 maximum population FAF is 2.8e-07, below the TP53 VCEP BS1 lower threshold of 0.0003.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no qualifying count of unrelated female carriers aged at least 60 years without cancer is available.	cspec
BS3	Not met	Not met: the VCEP worksheet assigns PS3_Moderate and records loss of function in three eligible assays, precluding a benign functional interpretation.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet cspec
BS4	Not assessed	Not assessed: no affected relatives with discrepant genotypes or documented non-segregation are available for this variant.	cspec
BP1	N/A	Not applicable: the TP53 VCEP excludes BP1 because truncating variants are not the primary disease mechanism.	cspec
BP2	N/A	Not applicable: the TP53 VCEP marks BP2 not applicable and provides no usable strength rule for trans/cis or phase evidence.	cspec
BP3	N/A	Not applicable: the TP53 VCEP explicitly designates BP3 as Not Applicable, and c.527G>T is a missense substitution rather than a repeat-region in-frame indel.	cspec
BP4	Not met	Not met: missense BayesDel 0.579613 exceeds the TP53 VCEP BP4 threshold of <0.16, so the SpliceAI max delta 0.004 cannot establish BP4.	cspec vcep_pp3_bp4_codes bayesdel spliceai
BP5	N/A	Not applicable: the TP53 VCEP excludes BP5, and no alternate molecular basis is documented for this case.	cspec
BP6	N/A	Not applicable: the TP53 VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.527G>T is a missense variant producing p.Cys176Phe, whereas BP7 is restricted to synonymous or qualifying intronic variants.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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